3,4-difluoro-{60 -pyrones having a 6-aromatic substituent

ABSTRACT

WHEREIN THE AROMATIC RADICAL HAS SIX TO 12 RING CARBONS, IS ATTACHED BY NUCLEAR CARBON TO THE 6-POSITION AND HAS UP TO FIVE HALOGEN, NITRO, HALO-LOWER ALKYL, LOWER ALKYL, OR LOWER ALKOXY SUBSTITUENTS. Also disclosed is a process for making the compounds and their usefulness in inhibiting both yeast and mold fungi.   Disclosed herein are pyrones of the formula

nited States Patent [191 England [4 1 Mar. 27, 1973 [54]3,4-DIFLUORO-a-PYRONES HAVING A 6-AROMATIC SUBSTITUENT David CharlesEngland, Wilmington,Del.

Assignee:- E. I. du Pont de Nemours and Company, Wilmington, Del.

Filed: Aug. 31, 1970 Appl. No.2 68,495

[75] Inventor:

US. Cl. ..260/343.5, 252/3012, 424/279,

260/544 F, 260/649 F llllll. Cl. ..C07d.7/l6 Field of Search .f...260/343.5

[56] References Cited UNITED STATES PATENTS ll/l967 3,351,653 Carr etal. ..260/343.5

Primary Examiner-Alex Mazel Assistant ExaminerAnne Marie T. TigheAttorney-James A. Costello [57] ABSTRACT Disclosed herein are pyrones ofthe formula 0 O Aromatie -F 16 Claims, No Drawings3,4-DIFLUORO-a-PYRONES HAVING A 6- AROMATIC SUBSTITUENT BACKGROUND OFTHE INVENTION SUMMARY OF THE INVENTION The novel compounds of thisinvention are 3,4- difluoro-a-pyrones of the formula wherein Ar IS anaromatic radical of SIX to 12 ring carbons, is attached by nuclearcarbon to the 6-position of The hydrolysis reaction proceeds in anaqueous medium, preferably one which is mildly basic. An aqueous sodiumbicarbonate medium is perfectly acceptable.

Preferred reaction temperatures are l25l75C. Although the reaction willproceed at temperatures below 100C., better rates are obtained above100C. Since the reactants are volatile at these elevated temperatures,closed systems are employed.

The substituted aromatic acetylenes that are reacted with theperfluoroacrylyl fluoride have substituents selected from the groupconsisting of halogen, nitro, halo-lower alkyl, lower alkyl or loweralkoxy. The perfluoroacrylyl fluoride is a known compound and referencethereto can be found, for instance, in Tarrant, J. Org. Chem., 28,1728-1730, (1963).

Numerous aromatic acetylenes are useful in the process taught herein.Such acetylenes include those that have one ring, two rings or a fusedring. In the first column of Table I are listed some of the substitutedaryl acetylenes that react with perfluoroacrylyl fluoride to give thenovel 3,4-difluoro-a-pyrones which are listed in the second column Thedifluoropyrones in the second column are novel, areuseful in inhibitingfungus growth and are included within the scope of this invention.

TABLE I Substituted aryl acetylenes Novel difluoro pyronesPhenylacetylene o-Nltmphcnylacctylcnn V V n1-Nitrophnnylacctylcnum'Chlorophcnylacctylcnc p-C hlorophenylacctylcnc o-Bromophcnylacetylm1c.m-Bromophcnylacetylcne pomophenylacetylene o-Iodophenylacetylenc.p-Iodophenylacetylene.

m-Fluorophenylacetylone. p-Flu0rophenylacetylene2,6-diehlorophenylacetylene 2,3;4,5,6'pentafluorophenylacetylvnep-Isopropylphenylacctylcnc p-E thylphenylacctylene3,4-dlamethoxyphenylaeetyl0 2,4-dirnethylphenylacetylene.

2,4,6-trimcthyl-3-bromophcnyla l 2,3,4,fi-tetramethylphenylacntylcnc5-chloro-2-nitrophenylacetylener v fi-bromo-2-nltrophcnylacetylenc4-phenylphenylacetylene o-Trlfiuoromethylphcnylacetylvnm-Trlfiuoromcthylphenylacetylene p-Trifiu mmethylphenylacetylcne i3,4-(11fluoro-fi-(p-triHuuronwthylphcnyD-a-pyrmw.

matic acetylene with perfluoroacrylyl fluoride followed by hydrolysis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The novel compounds areobtained according to the following reaction:

Ar-CECII CFr-"CFllF intermediate product intermediate product novelhydrolysis apyrones SPECIFIC EMBODIMENTS The following Examples areprovided to illustrate the invention and they should not be deemed tolimit the invention. All temperatures are in degrees centigrade.

EXAMPLE 1 3,4-Difluoro-6-phenyl-a-pyrone A mixture of 20 g (0.2 m) ofphenylacetylene and 18 ml (0.2 mole) of perfluoroacrylyl fluoride in asealed tube was heated in a steam bath for 48 hrs. Distillation of theblack reaction mixture yielded 8 g of low-boiling material and 22.4 g(49 percent) of material boiling at 56-66C. (0.5 mm). The latter was amixture of 1-phenyl-3 ,4 ,4-trifluoro- 1-phenylcyclobutenyl-4-carbonylfluoride) in a ratio of 2 to 1 (the pyran was concentrated in higherboiling fractions). A later fraction contained 2 g of1,2-difiuoro-4,5-diphenylbenzene,

Five g of the mixture was stirred in 25 ml of 10% aq NaHCO Filtrationgave 3.4 g of (3,4-difluoro-6-phenyl-a-pyrone). Recrystallization fromCCl. gave 2.1 g of the purified pyrone. Anal. ir: 5.80 p. (C=), 6.02,6.29, 6.35, 6.68 p. (aromatic and conjugated C=C H nmr: phenyl multiplet(centered) at 2.91; singlet proton doublet (J cps) to doublets (J 9 cps)3.421. F nmr: a doublet to doublets (wt 1) J 16, 5 cps at 167.6 ppm;doublet to doublets (wt 1)] 16, 9 cps at 121.8 ppm.

Anal. Calcd. for C H F O C, 63.51; H, 2.91; F,

18.27 Found;C, 63.44; H, 3.01; F, 18.13

EXAMPLE 2 3 ,4-Difluoro-6-(p-chlorophenyl)-a-pyrone A mixture of 13.6 g(0.1 m) of p-chlorophenylacetylene and 15.3 g (0.12 m) ofperfluoroacrylyl was heated in a Carius tube to 140 for 3 hrs. Afterremoval of 5 g of unreacted perfiuoroacrylyl fluoride, the black residuewas distilled yielding 6.0 g of black liquid, bp 74-82 (0.7 mm). Thedistillate was stirred with 30 ml of aq NaHCO Filtration gave 2.85 g ofmaterial which in cyclohexane/benzene was then passed through 100 g ofbasic (Activity 111) Woehlm alumina: Fraction 1 cyclohexane 0.09 g;Fraction 2 25 percent of benzene, 75 percent cyclohexane 0.89 g.Sublimation of Fraction 2 at 120 (0.25 mm) yielded 0.45 g (2 percent) of3,4-difluoro-6-(p-chlorophenyl)-a-pyrone, mp 123-125C.

Anal.

Calcd. for C H O F Cl: C, 54.47; H, 2.07; Cl, 14.61;

Found: C, 54.16; H, 2.34; C1 14.94; 54.55 22415.11

H nmr (CDC1 /TMS): quartet centered at 7.72 8 (wt quartet (J 5, 9 cps)centered at 6.74 8 (wt 1); hydration peak, 1.3 cps. F nmr (CDCl jFdoublet to doublet (J 9, 16 P 118 ppm (wt 1 doublet to doublet (J 5, 16cps), 164 pp EXAMPLE 3 3 ,4-Difluoro-6-(p-bromophenyl)-a-pyrone,

p-Bromophenylacetylene (18.1 g, 0.1 mole) and perfluoroacrylyl fluoride(15.3 g, 0.12 mole) were heated in a Carius tube to 150 for 3 hrs.Perfluoroacrylyl fluoride (9.3 g, 0.53 mole) was recovered bydistillation. Sublimation of the remaining tar at 100 (0.25 mm) yielded4.3 g of semisolid. This was stirred in 25 ml of 10 percent sodiumbicarbonate. Filtration gave 3.55 g of3,4-difluoro-6-(p-bromophenyl)-a-pyrone which when recrystallized from50 ml carbon tetrachloride gave 1.58 g (5 percent) of crystals, mp130.5-137 Anal.

Calcd. for C,,H -,O F,Br; C, 46.02; H, 1.75; F, 13.23

Found: C, 46.85; H, 2.04; F, 12.05 H nmr ((CCD ),Co/TMS): multipletsuperimposed on a doublet centered at 7.62 8. F nmr ((CD ),Co/F doubletto doublet (J 9, l6 cps) at 164 ppm (wt 1); doublet to doublet (J 5, l6cps) at 123 ppm (wt 1).

EXAMPLE 4 3,4-Difluoro-6-(p-tolyl)-a-pyrone 0 u QK 2* p-Tolyacetylene(11.6 g, 0.1 mole) and perfluoroacrylyl fluoride (15.3 g. 0.12 mole)were heated in a sealed tube on a steam bath for 12 hours. After removalof 6.0 g of unreacted perfluoroacrylyl fluoride, there was distilled 8.8g of a yellow-black semi-solid. This was stirred into 50 ml of 10percent sodium bicarbonate. The insoluble portion, collected byfiltration, sublimed at C (0.1 mm), was recrystallized twice frombenzene, and dried in vacuo over P 0 to give 4.3 g (10 percent) whitecrystals of 3,4-difluoro-6-(ptolylya-pyrone, mp l06-l07.

Anal. Calcd. for c r-1,0 13; C, 64.86; H, 3.63; F,

Found: C, 65.28; H, 3.85; F, 17.54 H nmr ((CD CO/TMS): quadruplet, 7.27,7.40, 7.71, 7.85 6 (wt 4); pair of doublets (J 4, 9 cps) centered at7.05 8 (wt 1); methyl singlet, 2.378 (wt 3); hydration peak, 2.088 (wt1).

F nmr ((CO CO/F doublets to doublets (J 9, 17 cps) centered at 125 ppm(wt 1). ir: CPI-3400 cm"; CO-l740 cm".

EXAMPLE 5 H nmr (CDCl /TMS): aromatic (wt 4); vinyl quartet (wt 1); twoCH singlets (total wt 6).

UTILITY 5 The effectiveness of selected novel compounds as3,4-Dif1uoro-6-(p-anisyD-a-pyrone. antifungal agents againstphycomycetes, ascomycetes, basidiomycetes and fungi imperfecti is shownin Table 0 H II. These compounds inhibit the growth of both yeast 10 andmold fungi including those that affect plants and warm-blooded animals.In addition to their use as fun- F gicides, the novel compounds hereinare fluorescent and are useful for applications requiring fluorescing Amixture of 10.1 g (0.75 m) of p-amsylacetylene agents v y and g ofPerfluereeerylyl fluende were 1 5 Studies of fungicidalactivity wereconducted on the heated to 140 for 4 hrs. After removal of low-boilersat novel compounds made according to Examples 1 to 6. room temperature,the black terfy resldue was As expected, effectiveness varies dependingon the Solved m Saturateq Nafleoa 501mm and e on compound being testedand on the genus and species of the steam bath. Th1s solution wasextracted with ether. fungus being treated and controlled Despite avaria The tar remaining upon dlstmatlcfn of the ether w tion ineffectiveness, all of the novel compounds of chroljlamgraphee on 300 gof f woehlm alumma Table I are effective against one or 'more of thefungi (Activity III) w1th 250 ml port1ons of 50 percent 'listedin TableIL eyelehexanebenzene- Fracuons 8 9 conmlned Because of their superioreffectiveness the preferred 8 of yellow erystels- Upon reerystelhzauonfrom CHC13, compounds of this invention are the products of Exam- Pyellow cryitals ples l, 2 and 4: 3,4-difluoro-6-(phenyl)-a-pyrone, 3,4-pymne'mp 134's were obtamed' diiluoro-6-(p-chlorophenyl)-a-pyrone, and3,4- Analdifluoro-6-(p-tolyl)-a-pyrone.

CalcdforCmHfloaFz: 6051; 9 Table II shows the minimum concentrations, in

Fmmd: 29, 5- micrograms/milliliter, of the novel compounds of Ex- I lamples l to 6 in a culture medium, that effectively in- (CDC13/TMS):Singlet (wt 3) 396; quartet (w hllzlt fungus growth after 1ncubat1on for72 hours at 4) 6.94, 7.09, 7.68, 7.83 8; quartet (wt 1) centered at 25C. The tests were conducted at concentrat1ons of 0, 654 0.01, 0.03, 0.1,0.3, 1, 3, 10, 30, 100 and 1,000 mlCtO- it: 1730 -1 1670 -d 1500 -1grams per milliliter in a potato dextrose medium with absence ofturbldity after mcubation showing inhibi- EXAMPLE 6 tion.

TABLE II In vitro activity 01 selected a-pyrones Physo BasidiomycetesAscomycetes (8 species) niycetes Fungi imperfeeti (7 species) Ex. (31*(b) (c) (d) 0 0 (11 10 0) (0 (k) 0) (m) (n) (o) (p) (q) The particularspecies of fungi, referred to in this table by lcltcr designation, aredescribed more fully in Table III.

3 ,4-Difluoro-6-( 2,4-dimethylphenyl )-a-pyrone.

A mixture of 20.49 g (0.16 m) of 75 percent 2,4- dimethylphenylacetyleneand 20.25 .g (0.16 m) of perfluoroacrylyl fluoride was heated in a steambath for 48 hrs. Distillation at 88 (0.9 mm) yielded a clear yellowliquid. This was stirred with excess saturated NaHCO solution. Themixture was extracted with CHCl After drying over MgSO the CHCl solutionwas evaporated to dryness. The pale yellow, crystals of 3,4-difluoro-6-(2,4-dimethylphenyl)-a-pyrone upon recrystallization from cyclohexaneweighed 8.5 g and melted at 83-84.5.

Anal. Calcd. for C13H|0F2021C, H, c, 66.50; H, 4.44

66.13 4.25 ir: C =0 1725,1760 cm Found:

Table III shows the various species of fungi whose growth has been shownto be effectively inhibited by the novel compounds of this invention.

American Type Culture Collection, Washington, DC.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:

1. A pyrone compound of the formula wherein Ar is selected from thegroup consisting of phenyl and biphenyl, is attached by nuclear carbonto the 6-position of the pyrone ring and has up to five substituentsselected from halogen, nitro, trifluoromethyl, lower alkyl of less thanfour carbons, or lower alkoxy of less than four carbons.

2. A compound according to claim 1, wherein the aromatic radical has upto three substituents.

3. A compound according to claim 1, 3,4-difluoro-6- phenyl-a-pyrone.

4. A compound according to claim 1, 3,4-difluoro-6-(p-chlorophenyl)-oz-pyrone.

5. A compound according to claim 1, 3,4-difluoro-6-(p-bromophenyD-a-pyrone.

6. A compound according to claim 1, 3,4-difluoro-6- (p-tolyl)-a-pyrone.

7. A compound according to claim 1, 3,4-difluoro-6- (p-anisyl)-a-pyrone.

8. A compound according to claim 1, 3,4-difluoro-6-(2,4-dimethylphenyl)-a-pyrone.

9. A process for making a compound of claim 1, comprising reactingperfluoroacrylyl fluoride with a substituted aromatic acetylene, whereinthe aromatic acetylene has up to five substitutents selected from thegroup consisting of halogen, nitro, trifluoromethyl, lower alkyl of lessthan four carbons, and lower alkoxy of less than four carbons, therebyforming an intermediate 2,2,3,4 tetrafluoro-6- aromatic-a-pyran, andhydrolyzing the intermediate in an aqueous medium.

10. A process according to claim 9, wherein the reaction temperature isbetween to C.

11. A process according to claim 9, wherein the aromatic acetylene isphenylacetylene.

12. A process according to claim 9, wherein the aromatic acetylene isp-chlorophenylacetylene.

13. A process according to claim 9, wherein the aromatic acetylene isp-bromophenylacetylene.

14. A process according to claim 9, wherein the aromatic acetylene isp-tolylacetylene.

15. A process according to claim 9, wherein the aromatic acetylene isp-anisylacetylene.

16. A process according to claim 9, wherein the aromatic acetylene is2,4-dimethylphenylacetylene.

- UL1flEAU 31.611330 Em wmn. wa'a'auau mnnrimrn er eenneenen Patent No.3.723.!!70 Dated 7 V375 Immrm David Charles England It is certified thaterror appears in the above--idenizifiM petent and that said LettersPatent are hereby corrected as eho'wn below:

r" Y I I w Col. 1, Table I, entry 21+, change "3 L-diamethoxyphenylacetylene" "co 3,L -dimeohoxyphenylacetylene 001. 1+,lines 1-2, change "Found: 0 9 16 H, 2,315; 01 14.95.; 54.55 2.21 15.11F, 15.113 15.153" to Found: c, 5 .16; H, 2.3a; 0.1, new F, l5.L,8 Y Y51%.55 2.21? 5 15.11 15.143 same column, line 36 change "((CCD Co/TMS)"to- -((CD3)2CO/TMS) and v I C03... line 22, change"cyelohexanebenze'ne"' to cyclohexane-benzene Signed and sealed this25th day of December 1973. I

(SEAL) Attest:

EDWARD M.FLETGI{ER,JB. g r RENE D. TEGIMEYER Acting Commissioner ofPatents Attesting Officer

2. A compound according to claim 1, wherein the aromatic radical has upto three substituents.
 3. A compound according to claim 1,3,4-difluoro-6-phenyl- Alpha -pyrone.
 4. A compound according to claim1, 3,4-difluoro-6-(p-chlorophenyl)- Alpha -pyrone.
 5. A compoundaccording to claim 1, 3,4-difluoro-6-(p-bromophenyl)- Alpha -pyrone. 6.A compound according to claim 1, 3,4-difluoro-6-(p-tolyl)-Alpha -pyrone.7. A compound according to claim 1, 3,4-difluoro-6-(p-anisyl)-Alpha-pyrone.
 8. A compound according to claim 1,3,4-difluoro-6-(2,4-dimethylphenyl)- Alpha -pyrone.
 9. A process formaking a compound of claim 1, comprising reacting perfluoroacrylylfluoride with a substituted aromatic acetylene, wherein the aromaticacetylene has up to five substitutents selected from the groupconsisting of halogen, nitro, trifluoromethyl, lower alkyl of less thanfour carbons, and lower alkoxy of less than four carbons, therebyforming an intermediate 2,2,3,4 tetrafluoro-6-aromatic-Alpha -pyran, andhydrolyzing the intermediate in an aqueous medium.
 10. A processaccording to claim 9, wherein the reaction temperature is between 100*to 175*C.
 11. A process according to claim 9, wherein the aromaticacetylene is phenylacetylene.
 12. A process according to claim 9,wherein the aromatic acetylene is p-chlorophenylacetylene.
 13. A processaccording to claim 9, wherein the aromatic acetylene isp-bromophenylacetylene.
 14. A process according to claim 9, wherein thearomatic acetylene is p-tolylacetylene.
 15. A process according to claim9, wherein the aromatic acetylene is p-anisylacetylene.
 16. A processaccording to claim 9, wherein the aromatic acetylene is2,4-dimethylphenylacetylene.